Animal studies show glaucoma drug shows promise against neurodegenerative diseases

A drug commonly used to treat glaucoma has been shown in zebrafish and mice to protect against the buildup of the protein tau in the brain, which causes various forms of dementia and is linked to Alzheimer's disease.

Researchers at the UK Dementia Research Institute at the University of Cambridge examined more than 1,400 clinically approved drug compounds using zebrafish that were genetically engineered to mimic so-called tauopathies. They discovered that drugs known as carbonic anhydrase inhibitors – which include the glaucoma drug methazolamide – clear tau buildup and reduce signs of the disease in zebrafish and mice that carry the mutated forms of tau that cause dementia in humans.

Tauopathies are neurodegenerative diseases characterized by the accumulation of tau protein “aggregates” in nerve cells in the brain.

These include forms of dementia, Pick's disease and progressive supranuclear palsy, in which tau is thought to be the primary pathogen, as well as Alzheimer's disease and chronic traumatic encephalopathy (neurodegeneration caused by repeated head injuries, as in football and rugby players was reported). The accumulation of tau is a consequence of the disease, but leads to degeneration of brain tissue.

Little progress has been made in finding effective drugs to treat these diseases. One option is to reuse existing medications. However, drug screening – where compounds are tested using disease models – usually takes place in cell cultures, but these do not capture many of the characteristics of tau accumulation in a living organism.

To get around this problem, the Cambridge team turned to zebrafish models they had previously developed. Zebrafish reach adulthood and can reproduce within two to three months, producing large numbers of offspring. Through genetic manipulation, it is possible to mimic human diseases because many genes responsible for human diseases often have equivalents in zebrafish.

In a study published in Natural chemical biologyProfessor David Rubinsztein, Dr. Angeleen Fleming and colleagues modeled tauopathy in zebrafish and examined 1,437 drug compounds. Each of these compounds is clinically approved for other diseases.

Dr. Ana Lopez Ramirez from the Cambridge Institute for Medical Research, Department of Physiology, Development and Neuroscience and the UK Dementia Research Institute at the University of Cambridge, joint first author, said: “Zebrafish offer a much more effective and realistic way of screening.” Drug compounds rather than with Cell cultures that function completely differently than living organisms. They also allow us to do this on a large scale, which is neither feasible nor ethical with larger animals like mice.

Using this approach, the team showed that inhibiting an enzyme called carbonic anhydrase – which is important for regulating acidity in cells – helped the cell get rid of the buildup of tau protein. This happened because the lysosomes – the “cell burners” – moved to the surface of the cell, where they fused with the cell membrane and “spit out” the tau.

When the team tested methazolamide on mice that had been genetically engineered to carry the human disease-causing tau mutation P301S, which leads to the progressive accumulation of tau aggregates in the brain, they found that the mice treated with the drug They performed better on memory tasks and showed improved cognitive performance compared to untreated mice.

Analysis of the brains of mice revealed that they actually had fewer tau aggregates and consequently a smaller reduction in brain cells compared to the untreated mice.

Co-author Dr. Farah Siddiqi, also from the Cambridge Institute for Medical Research and the UK Dementia Research Institute, said: “We were excited to see in our mouse studies that methazolamide lowers tau levels in the brain and protects against its further buildup.” -up. This confirms what we had shown when screening carbonic anhydrase inhibitors using zebrafish models of tauopathies.

Professor Rubinsztein, from the UK Dementia Research Institute and the Cambridge Institute for Medical Research at the University of Cambridge, said: “Methazolamide is a promising drug that is urgently needed to prevent the formation of dangerous tau proteins in the brain. Although we have only studied its effects in zebrafish and mice, so it is still early days, we at least know about the safety profile of this drug in patients.

“This allows us to move to clinical trials much more quickly than we would normally expect if we were starting from scratch with an unknown drug substance.”

“This shows how we can use zebrafish to test whether existing drugs could be used to combat various diseases, potentially significantly speeding up the drug development process.”

The team hopes to test methazolamide in various disease models, including more common diseases characterized by the accumulation of aggregatable proteins, such as Huntington's and Parkinson's diseases.